EurJ Clin Pharmacol (1991) 41:165-169 EuropeanJournalof ( ~ ) ~ [ ~ ( ~ ( ~ ]

003169709100194N

@Springer-Verlag 1991

Fosinopril pharmacokinetics and pharmacodynamics in chronic ambulatory peritoneal dialysis patients* T. W. B. Gehr t, D. A. Sica 1, D. M. Grasela 2, I. Fakhry 1, J. Davis 1, and K. L. Duchin 2 ~ Department of Medicine, Division of Nephrology, Medical College of Virginia, Richmond, Virginia and 2 Department of Human Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, USA Received: July 17, 1990/Accepted in revised form: January 19, 1991

Summary. The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated after the oral administration of 10 mg of fosinopril sodium to 6 chronic ambulatory peritoneal dialysis (CAPD) patients. The results from 1 patient are reported separately because of the presence of concomitant liver dysfunction. The mean tl/2, Cm~x,tmax, and A U C values for 5 of the C A P D patients were 19.5h, 202ng.m1-1, 4.8h, and 3.19 gg. h. m l - 1 respectively. Values for 1 C A P D patient with liver dysfunction were tl/2 of 65.4h, Cmax of 182ng.m1-1, t .... of 9h, and A U C of 18.1gg.h-m1-1. Peritoneal clearance of fosinoprilat was negligible, ranging from 0.07 to 0.23 ml. rain -1. Serum A C E activity remained significantly suppressed at 24 and 48 h after fosinopril sodium administration with mean decreases from baseline of 94.2% and 70.6%, respectively. A C E activity was suppressed to an even greater degree in the patient with liver dysfunction, remaining 97% inhibited 72 h after drug administration. Plasma renin activity (PRA) increased and plasma aldosterone concentrations decreased following drug administration. Mean arterial pressure did not change appreciably throughout the study. Dosage reductions may not be necessary in the majority of dialysis patients. Key words: Fosinopril; fosinoprilat, CAPD, ACE-inhibitor, pharmacokinetics, pharmacodynamics, peritoneal dialysis

Fosinopril sodium (SQ 28,555) represents a new class of orally effective, phosphorous containing angiotensin-converting enzyme (ACE) inhibitors which has been proven effective in the treatment of essential hypertension [1]. During or following absorption, fosinopril sodium is rapidly and extensively hydrolyzed to its pharmacologi* These studies were supported in part by the Bristol-Myers Squibb Pharmaceutical Research Institute and by NIH grant M01-RR00065

cally active diacid, fosinoprilat (SQ 27,519) [2]. To date, two additional minor metabolites of fosinopril sodium have been identified, a glucuronide conjugate and a p-hydroxy analog of the active diacid [2]. Excretion of fosinoprilat occurs approximately equally via renal and hepatic routes in patients without dysfunction of these organs [2]. After intravenous administration of SQ 27,519-[14C] to normal subjects, the 0 to 96 h recovery of radioactivity in urine averaged 44% of the dose. Faecal recovery under similar circumstances was 46% of the administered dose [2]. Since biliary clearance of fosinoprilat represents only 50% of total body clearance, it is important to investigate the pharmacokinetics and pharmacodynamics in patients with renal insufficiency. Accordingly, 6chronic ambulatory peritoneal dialysis (CAPD) patients were studied.

Patients and methods Six CAPD patients (5 M, 1 F) were studied after having given written informed consent (Table 1). These studies were approved by the Committee on the Conduct of Human Research of Virginia Commonwealth University. All patients were clinically stable and without evidence of either acute or chronic peritonitis. One patient

Table 1. Clinical characteristics of CAPD patients Patient Age (y)

Weight Sex (kg)

C.M. R.B. H.J. J.M. J.J. L.W.a

55 67 75 82 88 79

39 38 31 66 46 54

F M M M M M

Inulin clearance (ml. rain- 1) 2.3 0 3.8 3.9 4.6 0

Meds

Disease

2 5 1,3,4 1,6

NS CGN unknown NS DN HTN

abnormal liver function NS = nephrosclerosis; CGN = chronic glomerulonephritis; DN = diabetic nephropathy; HTN = hypertension; 1 = metoprolol; 2 = propranolol; 3 = diltiazem; 4 = isosorbide dinitrate; 5 = hydralazine; 6 = decadurabolin

T. W. B. Gehr et al.: Fosinopril kinetics in dialysis

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Time (h) Fig.1. Serum fosinoprilat concentrations (ng.mk ~) following the oral administration of fosinopril sodium (10 mg) to 5 CAPD patients (.) and 1 CAPD patient (L. W., o) with concomitant liver dysfunction. Values are expressed as mean with SD

(L.W.) was studied in the presence of enzymatic liver dysfunction and his pharmacokinetic data are reported separately. Approximately one week prior to study he had received an intramuscular injection of the anabolic steroid, decadurabolin. His serum bilirubin subsequently rose from 0.6 to 1.Tmg.d1-1 (normal range, 0.l.5mg.dl-X), SGOT increased from 25 to 56IU.1-1 (normal range, 0.40IU.l-~), and G G T increased to 162IU.1 -~ (normal range, 0-55 IU- 1-1), all prior to the administration of fosinopril sodium. Following discontinuation of decadurabolin, his liver function tests completely normalized. Each patient was admitted to the General Clinical Research Center of the Medical College of Virginia on the evening prior to study day i to allow for collection of baseline biological samples. Patients were managed with their routine peritoneal dialysis prescription which consisted of three, 2-1 daytime dialysate exchanges and one, 2-1 overnight exchange. Daytime exchanges contained either 1.5 or 2.5% dextrose and the overnight exchange either 2.5 or 4.25% dextrose. Patients fasted for at least 8 h prior to and for 4 h following drug administration. All antihypertensive medications were withheld the day prior to and throughout the study. A single 10-mg oral dose of fosinopril sodium was administered with 250 ml of tap water shortly after the instillation of the first peritoneal dialysis exchange. The patients were then asked to move around freely to facilitate dialysate mixing and to remain ambulatory for the succeeding 12 h. Venous blood samples were obtained just prior to (0 h) and at 0.5, 1, 2, 3, 4, 6, 9, 12, 16, 24, 48, 72, and 96 h after fosinopril sodium administration. In addition, just prior to fosinopril sodium administration a single dose of inulin (50 mg. kg-I) was given intravenously to estimate residual glomerular filtration rate. Urine was collected just prior to (0 h) and at 0-12, 12-24, 2448, 48-72, and 72-96 h following fosinopril sodium administration in those patients who were not anuric. Complete collections of dialysate fluid coinciding with the end of each exchange were made at 0-6, 6-12, 12-16, 16-24, 24-30, 30-36, 36-40, and 40-48 h. Blood pressure (ram Hg) and pulse rate (beats. min- 1) were measured before and at 0.5, 1, 3, 4, 6, 8,12, 24, 48, 72, and 96 h following drug administration. Mean arterial pressure (MAP) was calculated using the formula: [(2(Diastolic pressure) + Systolic pressure)/3],

Assays Concentrations of fosinoprilat were determined in serum, urine and dialysate by radioimmunoassay (RIA). Fifty gl of fosinoprilat antisera and 200 gl of 125I-fosinopril-histaminewere added to 25 gl of unknown serum samples. After mixing, the tubes were incubated for

2 h at room temperature. Separation of bound and free radioactivity was accomplished by the addition of polyethylene glycol-goat antirabbit gamma globulin followed by centrifugation. The resulting supernatants were decanted completely and counted in a standard well-type gamma scintillation counter with a discrimination setting of 20-50 KeV. Each sample was assayed in duplicate. Intraassay variability (C.V.) was 7.6% for a low control (6.7 ng- ml- 1), and 3.3% for a high control (41 ng. ml- 1), and interassay variability was 6.0% and 5.8% for the low and high controls, respectively. The limit of detection for this compound is 1 ng-ml-]. Since it has previously been determined that conversion of fosinopril sodium to fosinoprilat is virtually complete [2], unchanged fosinopril concentrations were not measured. Plasma renin activity (PRA) was determined by a RIA that measures the in vitro generation of angiotensin I. The assay used a generation time of 90 min and a system pH of 6.0 (GammaCoat, Clinical Assays, Cambridge, MA.) [3]. Plasma aldosterone levels were determined by a solid-phase R I A (Coat-A-Count, Diagnostic Products Corp., Los Angeles, CA.) [3]. Serum angiotensin-converting enzyme (ACE) activity was measured by a radioassay (Ventrex, Portland, ME.) [4]. In brief, the radiolabelled tripeptide 3H-HipGly-Gly was added to serum as substrate for angiotensin-converting enzyme followed by incubation for 30 rain and acidification with 0.5 N HC1. The reaction product 3H-Hip was then separated from unreacted substrate by extraction with Ventrex Scintillation Cocktail # 1 and counted. Angiotensin-converting enzyme was reported as the percentage of available substrate hydrolyzed per min. Plasma and urine inulin concentrations were determined by a colorimetric method employing anthrone, with spectrophotometric determination at an absorbance wavelength of 620 nm [5].

P h a r m a c o k i n e t i c analysis The results from 5 subjects are reported collectively (mean with SD) with patient L.W. presented separately. Model-independent pharmacokinetic parameters were calculated using standard procedures [6]. Area under the serum concentration vs. time-curve AUC(0.t) was determined from time 0 to time t by the linear trapezoidal method. A U C from time 0 to infinity was determined by summing AUC(0.t) and C~/)~z,where C~= concentration of fosinoprilat at the last sampling time point after drug administration and Xz = the absolute value of the slope of a least squares regression of the natural log of serum concentration vs. time in the terminal phase of drug disposition. The area under the first-moment curve AUMC(0-t) from time 0 to time t was determined using the linear trapezoidal method for the product of time and the concentration of fosinoprilat in serum vs. time. AUMC was calculated by A U M C ( 0 - t ) + [t(C0/)~z + Ct/)~z2] where t = final time at which a serum concentration data time point was available. Mean residence time (MRT) was calculated by AUMC/AUC. Elimination half-life (t1~2) was determined by ln2/Zz. Although the absolute bioavailability of fosinoprilat was not calculated as part of this study, apparent oral clearance, CL. f- ~, was also estimated, where f represented the fraction of the administered dose ultimately reaching the systemic circulation. CL. f i was calculated by Dose/AUC. The total oral clearance represents the sum of nonrenal, renal, and peritoneal clearances as expressed by the following equation: (CL-f-1)TOTAL= CLR + CLp + CLN. The clearance of fosinoprilat via peritoneal dialysis (CLp) was determined by CLp = CDE/AUC(0.48 h) where CDE = cumulative 48 h excretion of fosinoprilat in dialysate (gg). The renal clearance was determined by CLR = CUE/AUC(0-48 h)where CUE = cumulative 48 h urinary excretion of fosinoprilat (gg). The following parameters were also determined from visual inspection of the serum concentration vs time curves for individual patients: (1) the time to maximal serum concentration (tm~x)and (2) the maximal serum concentration (Cm~0. Peritoneal urea nitrogen clearance was also determined using standard clearance methodology.

167

T. W. B. G e h r et al.: Fosinopril kinetics in dialysis

Results

6

Fosinoprilatpharmacokinetics

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Fig.2. S e r u m angiotensin-converting enzyme ( A C E ) activity (units)

following oral administration of fosinopril sodium (10rag) to 5 CAPD patients (.) and 1 CAPD patient (L. W., o) with concomitant liver dysfunction. Values are expressed as mean with SD.

Pharmacodynamic analysis T h e relationship b e t w e e n fosinoprilat concentration and A C E inhibition as a p e r c e n t of baseline A C E activity ( % A C E I ) was assessed by means of a nonlinear regression analysis and the E ~

model [8]. E - (Em,x.F)/(ICs0+ F) where E is the % ACE inhibition from baseline, F is the fosinoprilat concentration, Emaxis the maximum possible effect, and ICs0is the fosinoprilat concentration required to produce 50% of Em~. Those parameters were estimated by the nonlinear least squares regression program PCNONLIN [9]. Table 2. M o d e l - i n d e p e n d e n t p h a r m a c o k i n e t i c p a r a m e t e r s for fosinoprilat after oral administration of fosinopril sodium (10 rag) to C A P D patients Pa- tl/2 tient (h)

Cmax tmax AUC MRT AUMC CL'f 1 (ng.m1-1) (h) (pg.h.ml 1) (h) (pg,h2.ml 1) (ml.min-1)

C.M. R.B, H.J. J.M. J.J.

319 195 144 148 205

14.4 27.6 25.2 9.5 20.8

6 6 6 3 3

6.47 4.29 1.65 1.53 1.99

16.2 21.3 15.3 10.1 13.3

105 91.7 25.3 15.4 26.4

25.8 33.7 100.9 108.9 83.8 70.6 (38.5)

Mean 19.5 202 (SD) (7.5) (70.8)

4.8 3.19 (1.6) (2.15)

15.2 52.7 (4.1) (41.9)

L.W, 65.4 182

9

95.9

18.06

1730

Table 3. Fosinoprilat a n d u r e a peritoneal dialysis clearance and cumulative fosinoprilat urinary excretion after oral administration of fosinopril sodium (10 rag) to C A P D patients CLBuN CDE/CUE AUC(0-48 h) (ml.min -1) (p,g) (gg.h.m1-1)

Fosinoprilatpharrnacodynamics

9.2

CL. f- ~ = a p p a r e n t oral fosinoprilat clearance

Patient

Mean serum fosinoprilat concentrations (n = 5) following a 10 mg oral dose of fosinopril sodium are represented in Fig. 1. One patient (L. W.) is depicted separately because of pharmacokinetic differences which were presumably related to his abnormal hepatic function. In that patient, serum fosinoprilat concentrations beyond 12 h were considerably higher than those values observed in the 5 other patients. Model-independent pharmacokinetic parameters are reported in Table 2 for the entire patient population (n--6), with the mean (SD) calculated for values obtained from the 5 patients with normal hepatic function. The tl/2, C .... Gax and A U C values for those 5 patients were 19.5 (7.5)h, 202 (70.8) ng.ml -z, 4.8 (1.6) h, and 3.19 (2.15)gg.h.m1-1, respectively. The pharmacokinetic parameter values are to be contrasted with those of L.W., where the tl~, Cm~x, tmax, and AUC0_~r were 65.4 h, 182 ng.m1-1, 9 h, and 18.1 gg h.m1-1, respectively. The calculated apparent oral clearance, C L . f 1, was 70.6 (38.5) ml. min -1 in the 5 CAPD patients with normal hepatic function and 9.2ml.min ~ in L.W. Mean residence time (MRT) was similarly affected by the presence of dual organ dysfunction, ie, 95.9 h in L. W. versus 15.2 (4.1) h in the other 5 patients. Table 3 reports both urea and fosinoprilat peritoneal clearance as well as the cumulative fosinoprilat urinary excretion and clearance. Peritoneal clearance, CLpER~roNEAL,of fosinoprilat over 48 h was negligible, ranging from 0.07 to 0.23 ml.min -~. Even though the estimated glomerular filtration rate [3.7 (1) ml-rain-a], as determined by inulin clearance, was low in the four patients producing urine, in all instances urinary excretion of fosinoprilat still exceeded that by dialysis.

CLp CLR (ml.min -1) (ml.min l)

C. M, R.B. H.J. J.M. J.J.

4.2 6.9 4.6 4.2 6.8

26.3/44.7 47.3/0 2.0/14.0 7.3/24.3 11.1/7.1

6,27 3,90 1,53 1,50 1.87

0.07 0.20 0.02 0.08 0,10

0.12 0.0 0.15 0.27 0.63

Mean (SD) L.W.

5.3 (1.4) 5.3

18.8/30.8 (18.3/27.8) 96.6/0.0

3.02 (2.07) 6.86

0,09 (0.07) 0.23

0.23 (0.24) 0.0

CLBvN = renal urea n i t r o g e n clearance C D E / C U E = cumulative dialysate excretion/urinary excretion CLp = p e r i t o n e a l fosinoprilat clearance CLR = renal fosinoprilat clearance

The change in A C E activity following fosinopril sodium administration is depicted in Fig.2. A C E activity remained significantly suppressed at 24 and 48 h with mean (SD) decreases of 94.2 (7.3) % and 70.6 (15.3) %, respectively. A C E activity was suppressed to an even greater degree in patient LW, remaining 97% inhibited even 72 h following the administration of fosinopril sodium. In the 5 CAPD patients with normal hepatic function, the serum fosinoprilat concentrations were related to the inhibition of serum A C E activity using the Em,x model. Fig. 3 depicts the profile from a single representative patient. The data sets from each patient were fitted independently and individual parameter estimates reported in Table 4. Mean (SD) Em~xwas 97.8 (3.42) % and ICs0 was 1.98 (0.87)ng.ml -~ for the 5 patients. Due to the prolonged, near maximal inhibition of serum ACE activity in the CAPD patient with hepatic dysfunction, the data from this patient was not able to be analyzed.

168

T. W. B. Gehr et al.: Fosinopril kinetics in dialysis

100.

the course of the study. Daily weights remained stable, decreasing from baseline by mean values of 0.1, 0.25, and 0.4 kg at 6, 24, and 48 h, respectively. No adverse reactions were noted during this single-dose study.

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Fig.3. Relationship between serum % A C E inhibition from baseline and serum fosinoprilat concentration (ng. m k 1) for i representative C A P D patient. The curve has been generated utilizing the Emaxmodel.

Plasma renin activity (PRA) and plasma aldosterone concentrations were determined in 4 of the 6 patients (Table 5). PRA increased [mean maximum % increase, 453 (646) %] and plasma aldosterone concentrations decreased [mean maximum % decrease, 45.1 (5.9) %] following the administration of fosinopril sodium. Blood pressure did not change appreciably following a single dose of fosinopril sodium even though additional blood pressure medications were not administered during Table 4. Individualparameter values for Emaxmodel relating serum

fosinoprilat concentration and % ACE inhibition in 5 CAPD patients Patient

(%)

ICsob (ng-ml -l)

92.5 101 98.3 101 96.8 97.8 (3.43)

2.35 1.18 1.51 1.54 3.34 1.98 (0.87)

Em~ ~

c.M. J.M. H.J. R.B. J.J. Mean (SD)

a Emax,Theoretical maximum percent inhibition of A C E activity b ICs0, Fosinoprilat serum concentration producing half maximal inhibition of A C E activity Table 5. Baseline P R A and aldosterone concentrations and maxim u m response following the administration of fosinopril sodium to CAPD patients Patient

Baseline Baseline Max. % Max. % PRA Aldosterone PRAIncrease Aldo. Decrease (ng AI.ml-l.h -1) (ng.dl -I) (%) (%)

R.B. H.J. J.M. J.J.

0.7 2.7 7.8 1.2a

9.3 17.3 83.9 32.7

28.6 77.8 301.3 1405.0

36.6 49.1 45.3 49.2

Mean (SD)

3.1 (3.2)

35.8 (33.5)

453.2 645.6

45.1 5.9

" P R A value done I h after fosinopril

The pharmacokinetics of fosinoprilat appear to be altered in the CAPD population. Although considerable interpatient variability in Cmaxexisted [202 (70.6) ng. ml-1], this value was comparable to that obtained in hemodialysis patients [197 (21)ng.m1-1] [10] but was substantially higher than the value obtained in healthy subjects [111 (24) ng. ml- 1] [2]. The higher Cmaxvalues observed in dialysis patients would be expected based on the reduction in renal clearance and lack of appreciable dialyzability of fosinoprilat in this patient population. The tmaxof 4.8 (1.6) h was somewhat longer than that of 2.7 (0.3) h observed in normal volunteers [2]. Time to peak concentration has also been noted to increase in conditions of renal impairment for other orally administered ACE inhibitors such as captopril [11], lisinopril [7, 12], and enalapril [12] even though enalaprilat is formed by esterolytic cleavage of enalapril. This phenomenon currently remains unexplained. The one CAPD patient with liver dysfunction displayed a tmaxvalue (9 h) which was markedly prolonged suggesting that fosinopril sodium absorption was delayed and/or the rate of hydrolysis to fosinoprilat slowed. The disposition of fosinoprilat as described by the parameters of tl/2 [19.5 (7.5) h] and MRT [15.2 (4.1) h] was similar to that seen in haemodialysis patients [tl/2, 28.3 (12.3) h; MRT, 16.3 (2.5) h] [10]. Compared to values obtained in patients with varying degrees of renal function, where tl/2 and MRT values were 15 and 7 h in healthy subjects (mean creatinine clearance, 99 ml-min-1), 18 and 12 h in patients with mild renal insufficiency (mean creatinine clearance, 61 ml. min- 1), 22 and 11 h in patients with moderate renal insufficiency (mean creatinine clearance, 32 ml. rain- 1), and 19 and 13 h in patients with severe renal insufficiency (mean creatinine clearance, 15 ml.min -1) [13], h/2 and MRT were similar among all patients with some degree of renal impairment, tl/2was similar, as well, to normal volunteers whereas the MRT values were approximately twice normal in all renally impaired patients. The elimination of fosinoprilat by peritoneal dialysis was insignificant, averaging 2.0 (1.4) % of simultaneously determined peritoneal urea clearance. This result is not unexpected since the drug is highly protein bound (95-98%) and has a relatively high molecular weight (427 daltons) [2]. Peritoneal dialysis clearances are not available for enalapril or lisinopril but have been shown to be comparably low for captopril [14]. After a single dose of fosinopril sodium, ACE activity fell precipitously and remained low (> 90% inhibition) for at least 24h. In the case of L.W., ACE activity remained low for at least 72 h, reflective of the diminished clearance of fosinoprilat. The prolonged inhibition of ACE activity in this study is consistent with detectable levels of fosinoprilat in serum up to 96 h post dose.

T. W.B. Gehr et al.: Fosinopril kinetics in dialysis The relationship between serum A C E inhibitor concentrations and A C E activity has most often been described by a linear model or via % A C E I log transformation [7, 15, 16]. These models have severe shortcomings which have been previously described [17]. A m o r e "physiologic", pharmacokinetic-pharmacodynamic model between fosinoprilat concentration and % A C E I is provided by the Emaxmodel [8]. Although there was some variability in individual ICs0 values for the five evaluable patients, the low values indicate that serum A C E activity is highly sensitive to the actions of the drug. The fact that serum fosinoprilat concentrations are much higher than the ICs0 for prolonged periods following drug administration indicates that there m a y be additional factors which are operative in the blood pressure lowering effects of the drug. Whereas C A P D patients have been reported to have relatively high basal unstimulated P R A and aldosterone concentrations [18, 19], basal levels of P R A and aldosterone concentration were normal in 3 of the 4 patients studied. As would be expected, P R A increased and plasma aldosterone concentrations decreased following the administration of fosinopril sodium. Though m e a n blood pressure trended downwards in 4 of the patients, m e a n blood pressure did not significantly decrease during the study. The one patient with a high baseline P R A value (J. M.) demonstrated the most significant drop in his m e a n blood pressure (113 to 76 m m H g ) which occurred at 8 h post dose. Without a placebo-treated group of patients, it is difficult to assess the single-dose antihypertensive effect of fosinopril sodium. As with other A C E inhibitors, dose modifications based solely on the single-dose pharmacokinetic profile are difficult to discern since the concentration of drug in serum often does not correlate with the desired effect of blood pressure reduction [15, 20]. The modest pharmacokinetic alterations observed in these patients compared to populations without end stage renal disease, and the lack of adverse effects associated with this drug would suggest that initial dose modifications should not be necessary in most C A P D patients. Particular caution m a y be indicated in those dialysis patients with concomitant liver dysfunction.

References 1. Duchin KL, Herman TS, O'Leary K, Tu J, Nichola P (1987) Steady-state (SS) kinetics of fosinopril in hypertensive patients. Clin Pharmacol Ther 41:227 2. Singhvi SM, Duchin KL, Morrison RA, Willard DA, Everett DW, Frantz M (1988) Disposition of fosinopril sodium in healthy subjects. Br J Clin Pharmacol 25:9-15 3. Gehr TWB, Sica DA, Brater DC, Davis J, Fakhry I (1988) Furosemide pharmacokinetics and pharmacodynamics in renal transplantation. Clin Pharmacol Ther 43:54%553 4. Swanson BN, Stauber KL, Alpaugh WC, Weinstein SH (1985) Radioenzymatic assay of angiotensin-converting enzyme inhibitors in plasma and urine. Anal Biochem 148:401-407

169 5. Fuhr J J, Daczmarczyk J, Kruttgen CD (1955) Eine einfache colorimetrische Methode zur Inulinbestimmung ffir Nieren-Clearance-Untersuchungen bei Stoffwechselgesunden und Diabetikern. Klin Wochenschr 33:72%730 6. Gibaldi M, Perrier D (1982) Pharmacokinetics, 2. ed. Dekker, New York, pp 40%417 7. Van Schaik BAM, Geyskes GG, Boer P (1976) Lisinopril in hypertensive patients with and without renal failure. Eur J Clin Pharmacol 32:11-16 8. Donnelly R, Meredith PA, Elliott HL, Reid JL (1990) Kineticdynamic relations and individual responses to enalapril. Hypertension 15:301-309 9. Metzler CM, Weiner DL (1989) PCNONLIN user's guide, 3 ed. Statistical Consultants, Lexingtion, KY 10. Duchin K, Kripalani K, Kramer E Sica DA (1989) Disposition and pharmacodynamics of fosinopril sodium (FS) and its diacid in hemodialysis (HD) patients. Kidney Int 35:245 11. Drummer OH, Workman BS, Miach PJ, Jarrott B, Louis WJ (1987) The pharmacokinetics of captopril and captopril disulfide conjugates in uraemic patients on maintenance dialysis: Comparison with patients with normal renal function. Eur J Clin Pharmacol 32:267-271 12. Kelly JG, Doyle GD, Carmody M, Glover DR, Cooper WD (1988) Pharmacokinetics of lisinopril, enalapril and enalaprilat in renal failure: effects of haemodialysis. Br J Clin Pharmaco126: 781-786 13. Hui KK, Duchin KL, Kripalani KJ, Chan D, Kramer PK, Yonogowa N (1991) Pharmacokinetics of fosinopril in patients with various degrees of renal function. Clin Pharmacol Ther 49:454 14. Fujimura A, Kajiyama J, Ebihara A, Iwashita K, Nomura Y, Kawahara Y (1986) Pharmacokinetics and pharmacodynamics of captopril in patients undergoing continuous ambulatory peritoneal dialysis. Nephron 44:324-328 15. Biollaz J, Schelling JL, Jocot des Combes B, Brunner DB, Desponds G, Brunner HR, Ulm EH, Hichens M, Gomez HJ (1982) Enalapril maleate and a lysine analogue (MK-521) in normal volunteers; relationship between plasma drug levels and the renin angiotensin system. Br J Clin Pharmacol 14:363-368 16. Johnston CI, Jackson BJ, Larmour I, Cubella R, Casley D (1984) Plasma enalapril levels and hormonal effects after short- and longterm administration in essential hypertension. Br J Clin Pharmacol 18: 233S-238S 17. Holford NHG, Steiner LB (1981) Understanding the dose-effect relationship: Clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 6:42%453 18. Zager PG, Frey H J, Gerdes BG (1983) Plasma 18-hydroxycorticosterone during continuous ambulatory peritoneal dialysis. J Lab Clin Med 102:604~512 19. Glasson P, Favre H, Vallotton M (1982) Response of blood pressure and the renin-angiotensin-aldosterone system to chronic ambulatory peritoneal dialysis in hypertensive end-stage renal failure. Clin Sci 63: 207S-209S 20. Fruncillo R J, Rocci ML, Vlasses PH Jr., Mojaverian R Shepley K, Clementi RA, Oren A, Smith RD, Till AE, Riley LJ Jr., Krishna G, Narins RG, Ferguson RK (1987) Disposition of enalapril and enalaprilat in renal insufficiency. Kidney Int 31 [Supp120]: $117$122

T. W. B. Gehr, MD Division of Nephrology Medical College of Virginia MCV Station Box 160 Richmond, Virginia 23298-0001, USA